The sinoatrial node (SAN) is the primary pacemaker of the heart and functions to establish the heart rate throughout life1,2. Failure of SAN function due to congenital disease or aging results in bradycardia, which eventually leads to circulatory collapse. The standard treatment for SAN failure patients is implantation of an electronic pacemaker that has disadvantages including lack of hormonal responsiveness and risk of infections due to electronic leads3,4. Biological pacemakers derived from human pluripotent stem cells (hPSCs) could represent a promising alternative since advances in the stem cell field now allow efficient production of hPSC-derived cardiomyocytes (90%)5-7. The cardiomyocyte population consists of a mixture of ventricular, atrial and pacemaker cells.8,9 However, there are currently only limited strategies to specifically generate and isolate each of these cardiomyocyte subtypes.
In Zhu et al.23, the progenitor cells having nodal phenotype produced from hPSCs were increased by inhibition of NRG-1β/ErbB signaling. Pacemaker cells were selected from hPSC-derived cardiomyocyte populations using a GATA-6 promoter/enhancer eGFP reporter. The type of nodal cells was not specified. Secondary atrioventricular (AVN) cells can be identified with a GATA-6 reporter in the mouse heart, as shown in Davis et al.24 
In Kehat et al.30, cardiomyocyte cell grafts were generated from hPSCs in vitro using an embryoid body differentiating system and were transplanted into hearts of swine with atrioventricular block without selection for pacemaker cells. Only in 6 out of 13 animals a stable ectopic rhythm activated by the human transplant could be seen.
In Ionta et al.31, it was reported that overexpression of SHOX2 by transduction with an adenoviral vector expressing human SHOX2 during mouse ESC differentiation upregulated the pacemaker gene program, resulting in enhanced automaticity in vitro and induced biological pacing upon transplantation in a rat.